2-148178611-A-C

Variant names:

• chr2-148178611-A-C
• rs12465610
• NM_001378120.1:c.-924-89A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378120.1(MBD5):​c.-924-89A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 388,598 control chromosomes in the GnomAD database, including 25,987 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8363 hom., cov: 32)
  • Exomes 𝑓: 0.38 (17624 hom.)
• Consequence: MBD5 NM_001378120.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0520
• Publications: 2 publications found

Genes affected

MBD5 (HGNC:20444): (methyl-CpG binding domain protein 5) This gene encodes a member of the methyl-CpG-binding domain (MBD) family. The MBD consists of about 70 residues and is the minimal region required for a methyl-CpG-binding protein binding specifically to methylated DNA. In addition to the MBD domain, this protein contains a PWWP domain (Pro-Trp-Trp-Pro motif), which consists of 100-150 amino acids and is found in numerous proteins that are involved in cell division, growth and differentiation. Mutations in this gene cause an autosomal dominant type of cognitive disability. The encoded protein interacts with the polycomb repressive complex PR-DUB which catalyzes the deubiquitination of a lysine residue of histone 2A. Haploinsufficiency of this gene is associated with a syndrome involving microcephaly, intellectual disabilities, severe speech impairment, and seizures. Alternatively spliced transcript variants have been found, but their full-length nature is not determined. [provided by RefSeq, Jul 2017]

MBD5 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal dominant 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-148178611-A-C is Benign according to our data. Variant chr2-148178611-A-C is described in ClinVar as [Benign]. Clinvar id is 1262738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.446 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBD5	NM_001378120.1	c.-924-89A>C		intron_variant	Intron 1 of 13	ENST00000642680.2	NP_001365049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MBD5	ENST00000642680.2	c.-924-89A>C		intron_variant	Intron 1 of 13		NM_001378120.1	ENSP00000493871.2

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46862 AN: 152000 Hom.: 8368 Cov.: 32

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.420

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.429

Gnomad EAS AF: 0.462

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.389

Gnomad OTH AF: 0.335

GnomAD4 exome AF: 0.381 AC: 90037 AN: 236480 Hom.: 17624 AF XY: 0.382 AC XY: 45877 AN XY: 120110

African (AFR) AF: 0.117 AC: 810 AN: 6938

American (AMR) AF: 0.361 AC: 2605 AN: 7210

Ashkenazi Jewish (ASJ) AF: 0.441 AC: 3908 AN: 8852

East Asian (EAS) AF: 0.443 AC: 9782 AN: 22080

South Asian (SAS) AF: 0.302 AC: 646 AN: 2140

European-Finnish (FIN) AF: 0.366 AC: 7304 AN: 19932

Middle Eastern (MID) AF: 0.447 AC: 549 AN: 1228

European-Non Finnish (NFE) AF: 0.385 AC: 58683 AN: 152398

Other (OTH) AF: 0.366 AC: 5750 AN: 15702

GnomAD4 genome AF: 0.308 AC: 46866 AN: 152118 Hom.: 8363 Cov.: 32 AF XY: 0.307 AC XY: 22806 AN XY: 74360

African (AFR) AF: 0.118 AC: 4915 AN: 41530

American (AMR) AF: 0.341 AC: 5216 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.429 AC: 1487 AN: 3468

East Asian (EAS) AF: 0.461 AC: 2385 AN: 5168

South Asian (SAS) AF: 0.301 AC: 1452 AN: 4826

European-Finnish (FIN) AF: 0.358 AC: 3772 AN: 10548

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.389 AC: 26421 AN: 67978

Other (OTH) AF: 0.334 AC: 704 AN: 2110

Alfa AF: 0.334 Hom.: 1223

Bravo AF: 0.304

Asia WGS AF: 0.316 AC: 1095 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.3
DANN	Benign	0.76
PhyloP100		-0.052
PromoterAI		0.011	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12465610; hg19: chr2-148936180; COSMIC: COSV69486586; COSMIC: COSV69486586;